Adamantyl derivatives of phenothiazines



United States Patent 3,320,249 ADAMANTYL DERIVATIVES OF PHENO- THIAZINESJack Bernstein, New Brunswick, N.J., assignor to Olin Mathieson(Zhemical Corporation, New York, N.Y., a corporation of Virginia N0Drawing. Filed July 9, 1965, Ser. No. 470,930 14 Claims. (rCl. 260243)This invention relates to new compounds of the formula (I) Hz and toacid-addition and quaternary ammonium salts thereof.

In Formula I, R and R each is hydrogen, halo, lower alkyl, phenyl orlower alkoxy. R and R each is hydrogen, halogen, trifiuoromethyl, loweralkyl or lower alkoxy. The symbol m represents an integer from 0 to 7,preferably 0, 1 or 2. Z represents a nitrogen containing group such asthose of the formula II l or wherein R is hydrogen or lower alkyl, and nis 1 or 2, e.g., amino, lower alkyl-amino, such as methylamino,ethylamino or the like, piperazino, lower alkylpiperazino such as 2- orS-methylpiperazino, and di-lower alkylpiperazino, such as2,5-dimethylpiperazino. The attachment to the alkylene group is througha nitrogen atom.

The halogens represented by R, R R and R include chlorine, bromine,iodine and fluorine, but the first two are preferred. Lower alkyl groupsrepresented by the symbols include straight and branched chain aliphaticgroups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,t-butyl, amyl, isoamyl and the like. Methyl and ethyl are preferred. Thelower alkoxy groups are ether groups having alkyl groups of theforegoing character attached to the oxygen.

The lower alkylene groups are straight or branched chain, divalentaliphatic hydrocarbon groups of the same type as the lower alkyl groupsreferred to above. Two to three carbon chains are preferred.

The new compounds of this invention may be produced by a variety ofmethods. According to one method, a substituted or unsubstitutedadamantanamine, i.e., one in which R, R or R are hydrogen or any of theother substituents represented by the respective symbols, is reactedwith a haloacyl halide to obtain a haloalkanoyladamantanamine, which isreduced, e.g., with lithium aluminum hydride, to the correspondingadamantylaminoalkyl halide. The last is then reacted with a substitutedor unsubstituted phenothiazine to obtain the product of Formula I.

Alternatively, the same starting material is converted to anadamantylamino alkanol, e.g., with an alkylene oxide such as ethyleneoxide, propylene oxide or the like,

ice

and the alkanol is converted to the corresponding alkyl halide, e.g.,with a thionyl halide such as thionyl chloride or thionyl bromide. Thenthis product is reacted with a substituted or unsubstituted2-(trifiuoromethyl)phen0- thiazine to obtain the same product as by thefirst procedure.

Suitable starting materials for compounds of formula I include, forexample, l-adamantylamine, 3-methyl-1- adamantylamine,3-phenyl-l-adamantylamine, S-methoxyl-adamantylamine,3-ethoxy-l-adamantylamine, 3-fluoro-, 3-chloro-, 3-bromoand3-iodo-l-adamantylamine, 3,5- dimethyl-l-adamantylamine, as well as theadamantyllower alkylamines and N-alkyl compounds corresponding to theabove.

These amines may be prepared by the reduction of anN-acyl-adamantylamine such as N-(1-adamantyl)acetamide with lithiumaluminum hydride or by the alkylation of an adamantylamine such asl-adamantylamine with an alkyl halide such as methyl iodide.

A further alternate comprises reacting an N-alkylacylamide, such asN-ethylacetamide, with a haloadamantane such as 1-bromo-adamantane andhydrolyzing the N- ethyl-N-(1-adamanty1)-acetamide to theN-ethyl-l-adamantyla-mine.

Reduction of an adamantanecarboxamide such as N-methyl-l-adamantanecarboxamide with lithium aluminum hydride yieldssuitable starting amines for those derivatives in which in is one.Similarly, the reduction of an adamantanylacetamide yields derivativesin which m is two.

Phenothiazines which may be utilized to produce compounds of Formula Iinclude, for example, 2-chlorophenothiazine, 2 methoxyphenothiazine, 2(trfluoromethyl) phenothiazine, Z-tertiarybutylphenothiazine,4-(trifluoromethyl) phenothiazine, 3-chlorophenothiazine, Z-methoxy-7-chlorophenothiazine, 2-fluorophenothiazine, etc.

Preferred compounds of this invention are those wherein Z represents-N-methyl or piperazinyl, the lower alkylene group has 2 to 3 carbonatoms, R is trifluoromethyl, especially in the 2-position; R, R and Rare all hydrogen, R is lower alkyl and m is O to l.

The bases of Formula I form acid-addition salts with a variety ofinorganic and organic acids. Such salts include, for example, thehydrohalides, e.g., hydrochloride, hydrobromide, etc., sulfate,phosphate, nitrate, arylsulfonates, e.g., camphorsulfonatebenzenesulfonate, toluenesulfonate, etc., citrate, oxalate, ascorbate,acetate, tartrate, salicylate and the like. It is frequently convenientto isolate the compound by forming the acid salt and precipitating in amedium in which it is insoluble. The free base may then be obtained byneutralization. The bases also form quaternary ammonium salts withquaternizing agents which are acceptable for pharmaceutical use, e.g.,lower alkyl halides such as methyl chloride, methyl bromide, ethylchloride, etc., lower alkyl sulfates such as methyl sulfate, ethylsulfate, etc., monocyclic aryl (lower alkyl) halides and sulfates suchas benzyl chloride, benzyl sulfate, etc. This is accomplished byreacting the base with the alkyl halide, sulfate, or the like.

The compounds of this invention are therapeutically active substanceswhich possess oentral depressant activity. They are useful in thetreatment of conditions such as Parkinsonism or as tranquilizers,sedatives or anti-emetics. They may be administered orally orparenterally in the form of tablets, capsules, elixirs, injectables orthe like by incorporating the appropriate dosage (e.g., 10 to 250 mg.)of the base of Formula I or a physiologically acceptable acid-additionsalt or quaternary ammonium salt thereof in a conventional vehicletogether with excipients, lubricants, preservatives, stabilizers and thelike, as required according to accepted pharmaceutical practice.

The following examples are illustrative of the invention. Alltemperatures are expressed on the centigrade scale.

EXAMPLE 1 propyl] 2 (irifluoromethyl) phenathiazine hydrochloride (a)Preparation of N (1 adamantyl) 3-chloro-N- methylpropionamide.With icecooling and stirring, 37.1 grams of fi-chloropropionyl chloride in 100ml. of anhydrous benzene is added dropwise to 100 grams of 1-(methylamino)adamantane in 200 ml. of anhydrous benzene. The reactionmixture is then refluxed for 5 hours, filtered and the filtrate Washedwith water and dried over anhydrous magnesium sulfate. The ether isremoved by distillation and theN-(l-adamantyl)-3-chloro-N-methylpropionamide thus obtained may be usedwithout further purification. If desired, the product may be purified byfractional distillation.

(b) Preparation of N-(3 -chlr0propyl) N methyl- 1-adamantanamine.--To 38grams of lithium aluminum hydride in 200 ml. of anhydrous ether is addeddropwise a solution of 25 grams of N-(1-adamantyl)-3chloro-N-methylpropionamide in 400 ml. of anhydrous ether. The mixture is thenrefluxed for one hour, cooled in ice, treated with 2.5 ml. of water andthen 2.5 ml. of 20% aqueous sodium hydroxide. The mixture is filteredand dried over anhydrous potassium carbonate. The ether is removed bydistillation and the residue is fractionally dis tilled under reducedpressure to yield the desired N-(3- chloropropyl-N-methyll-adamantanamine.

(c) Preparation of 10 [3 (N methyl-1 -aa'amantylamino) propyl] 2(trifluoromethyl)phenothiazine hydr0chl0ride.A mixture of 26.7 grams of2-(trifluoromethyl)-phenothiazine, 4.1 grams of sodamide, 29 grams ofN-(3-ch1oropropyl)-N-methyl-1-adamantanamine and 500 ml. of dry xyleneis stirred and refluxed for 17 hours. The hot solution is filtered andthe filtrate is coneentrated under reduced pressure. The residue isdissolved in 400 ml. of ether and the solution is extracted with 5%aqueous hydrochloric acid (3 portions of 150 ml. each). The hydrochloricacid extracts are combined, washed with ether and then made stronglyalkaline with 40% aqueous sodium hydroxide. The mixture is thenextracted with ether, the ether extracts dried over anhydrous magnesiumsulfate and concentrated by distillation. The residue is distilled underreduced pressure to yield the desired N- [S-(N-methyl-l -adamanthylaminopropyl] -2- (trifluoromethyl)phenothiazine.

The base is dissolved in 300 ml. of anhydrous ether and treated with aslight excess of ethereal hydrogen chloride. The precipitated solid isfiltered and dried to yield the desired hydrochloride of N [3 (N-methyl-1-adamantylamino)propyl] 2 (trifluoromethyl)phenothiazine. Thehydrochloride may be further purified by crystallization from a mixtureof alcohol and ether.

EXAMPLE 2 Preparation of [2 (N-meihyl 1 adamantylamino)elhyl]-2-chlorophenothiazine hydrochloride (a) Preparation ofZ-(N-methyl 1 adamantylamino) ethan0l.A 140 m1. stainless steel bomb ischarged with 16.5 grams of N-methyl-l-adamantylamine, 5.0 grams ofethylene oxide and 50 ml. of aqueous tetrahydrofuran and heated at 70for 12 hours. The solvent is removed by distillation and the residuefractionally distilled to yield the desired 2 (N methyll-adamantylamino) ethanol.

(b) Preparation of N (2 bromoethyl) N-methyl- 1 adamantylaminehydrobromide.-A solution of 20.9 grams of2-(N-methyl-l-adamantylamino)-ethanol in 100 ml. of chloroform is cooledto 0 and a solution of 30 grams of thionyl bromide in 150 m1. ofchloroform is added dropwise with vigorous stirring, while thetemperature is maintained at 0-5. The reaction mixture is then allowedto warm to room temperature, diluted with anhydrous ether and filteredto recover the N-(2-bromoethyl)-N-methyl-l-adamantylamine hydrobromide.This may -be recrystallized from a mixture of ethanol and ether.

(c) Preparation of 10 [2 (N-meihyl-I-adamantylamino)ethyl]Z-chlorophenothiazine hydrochloride.A mixture of 16.5 grams of2-chlorophenothiazine and 3.5 grams of sodamide in 400 ml. of drytoluene is refluxed gently for 6 hours while a slow stream of nitrogenis bubbled through the mixture. The reaction mixture is then cooled anda solution of N-(2-bromoethyl)-N- methyl-l-adamantylarnine in drytoluene (prepared from 35 grams ofN-(2-bromoethyl)-N-methyl-l-adamantylamine hydrobromide by extracting,with toluene, an aqueous solution of the amine that has been madealkaline with potassium carbonate and drying the toluene extracts overanhydrous magnesium sulfate) is added dropwise with vigorous stirring.The reaction mixture is then refluxed for an additional 6 hours,filtered and the filtrate concentrated under reduced pressure to removethe solvent. The residue is dissolved in chloroform, refluxed withdecolorizing carbon, and filtered hot. The filtrate is concentratedunder reduced pressure and the residue distilled under reduced pressureto yield the desired 10- [2(N-methyl-l-adamantylamino)ethyl]-2-chlorophenothiazine.

The hydrochloride is prepared by treating an ethereal solution of thebase with an equivalent of ethereal hydrogen chloride.

Following the procedure of Example 2 but substituting the indicatedsubstituted phenothiazine for the Z-chlorophenothiazine in part (c),there is formed the designated 10 [2 (N-methyl-l-adamantylamino)ethyl]-R-phen0- thazine hydrochloride.

EXAMPLE 9 Preparation of 10-[2-(N-ethyl-3-methyl Iadamantylamin0)ethyl]-2-chlorophenoihiazine hydrochloride (a)Preparation of I-ethylamino 3 methyladamantane.A mixture of 60 grams ofN-ethylacetamide, 45 grams of 1-bromo-3-methyladamantane and 60 grams ofsilver sulfate is heated at for 1 hour. The cooled mixture is treatedwith 100 ml. of Water and extracted with ether. The ether extracts arecombined, dried over anhydrous magnesium sulfate and concentrated underreduced pressure to yield l-(N-ethylacetamido)-3-methyladamantane.

A mixture of 12 grams of 1-(N-ethylacetamido)-3- methyladamantane, 12grams of sodium hyroxide and ml. of diethyleneglycol is refluxed for 5hours. The cooled mixture is poured into 1 liter of water and extractedwith ether. The combined ether extracts are dried over anhydrouspotassium carbonate and the ether removed by distillation to yield the1-ethylamino-3-methyladamantane.

(b) Preparation of 10-[2(N-et/Iyl-3-methyl-I-adamantylamino)ethyl]-2chlorophenothiazine hydrochl0ride. Following the procedure of Example 2but substituting an equivalent amount of the1-ethylamino-3-methyladamantane for the N-methyl-l-adamantylamine inpart (a), there is obtained 10-[2-(N-ethyl-3-methyl-l-adamantylamino)ethyl] -2-chlorophenothiazine hydrochloride.

EXAMPLE Preparation of 1 0-[3-(N-methyZ-S-methoxy-Z-adamantylmethylamin0)pr0pyl] 2(trifluoromethyl)pJzenothzazine hydrochloride (a) Preparation ofN-methyl-3-meth0xy 1 adamantanecarb0xamide.-A mixture of 10 grams of3-methoxyl-adamantanecarboxylic acid and ml. of thionyl chloride areheated under reflux for minutes. The excess thionyl chloride is remoevdby distillation under reduced pressure. Ten ml. of anhydrous benzene isadded and the benzene removed by distillation under reduced pressure.

The cooled residue is treated with a solution of methylamine in benzene.After several hours, the precipitated solid is removed by filtration,and the filtrate concentrated under reduced pressure to yieldN-methyl-3-methoxy-1- adamantanecarboxamide.

(b) Preparation of N-(3-meth0xy-1-adamantylmethyl) methylamine.-Asolution of 10 grams of N-methyl-3- methoxy-l-adamantanecarboxamide inanhydrous ether is added slowly to a suspension of lithium aluminumhydride in anhydrous ether. After the addition is completed, thereaction mixture is heated to gentle reflux for 4 hours and is thencooled. Water is added dropwise to decompose the unreacted lithiumaluminum hydride, followed by a 10% sodium hydroxide solution. Theprecipitated solids are removed by filtration and Washed with ether. Thecombined ether solutions are dried over anhydrous magnesium sulfate andconcentrated under reduced pressure to yield the N(3-methoxy-l-adamantylmethyl) methylamine.

(c) Preparation of10-[3-(N-methyl-3-meth0xy-1-aa'amantylmethylamino)propyl] 2(triflu0r0methyl)phen0- thiazine hydrochbride-Following the procedure ofExample 1 but substituting an equivalent amount of N-(3-methoxy-l-adamantylmethyl)methylamine for the l-methylaminoadamantane inpart (a), there is obta ned 10-[3- (Nmethyl-3-methoxy-1-adamantylmethylam1no)propyl-2-(trifluoromethyl)phenothiazine hydrochloride.

Similarly, by replacing the 3-methoxy-1-adamantanecarboxylic acid withan equivalent amount of 3-pheny1-ladamantanecarboxylic acid in part (a),there is obtained 10 [3 (N-methyl-3-phenyl-l-adamantylmethylamino)propyl] 2-(trifluoromethyl)phenothiazine hydrochloride. Replacement with3-bromo-l-adamantanecarboxyllc acid yields the corresponding l0-[3-(Nmethyl-3-bromo-1-adamantylmethylamino)propyl]2-(trifluoromethyl)phenothiazine hydrochloride.

EXAMPLE 1 1 Preparation of 10 {3-[4-(Z-adamantylmethyl)-J-piperazinyl]propyl}-2-(trifluoromethyl) phenothiazine maleic acid salt (21)Preparation of 10-{3- [4-(1-adamant0yl)-Z-piperazinyl]pr0pyl}-2(triflaoromethyl)phen0thiazine.To a solution of 20 grams of10-[3-(1-piperazinyl)propyl]-2- (trifluoromethyl)phenothiazine inanhydrous toluene, there is added dropwise with vigorous stirring, asolution of 10 grams of l-adamantanecarboxylic acid chloride. Themixture is then refluxed for 1 hour, cooled and dilute sodium hydroxidesolution added. The mixture is shaken vigorously and the organic layeris separated. The aqueous layer is extracted several times with etherand the toluene and ether extracts combined. The combined extracts aredried over anhydrous magnesium sulfate, and then concentrated underreduced pressure to yield the desired product.

(b) Preparation of 10 {3-[4-(1-adamantylmethyl)-1- piperazinyflpropyl} 2(trifluoromethyl)phenothiazine, maleic acid salt.-To 3.8 grams oflithium aluminum hydride in 200 ml. of anhydrous ether is added dropwisea solution of10-{3-[4-(l-adamant0yl)-1-piperazinyl]propyl}-2-(triflu-oromethyl)phenothiazinein anhydrous ether. The mixture is refluxed for 1 hour, cooled in ice,treated with 2.5 ml. of water and then 2.5 ml. of 20% aqueous sodiumhydroxide. The mixture is filtered, dried over anhydrous potassiumcarbonate and then concentrated under reduced pressure to remove thesolvent.

The residue is dissolved in dry acetonitrile and treated with anequivalent amount of a Warm solution of maleic acid in acetonitrile.Addition of anhydrous ether completes the precipitation of the saltwhich is recovered by filtration.

EXAMPLE 12 Preparation of 10- {3- [2- 1 -adamantyl) ethylamina]pr0pyl}-2-( trifluoromethyl) phenothiazine hydrochloride (a) Preparationof 10-[3(I-adamantylacetamida)propyl]-2(trifla0r0methyl)phenothiazine.To a solution of 16.3 grams of10(3-aminopropyl)-2-(trifluoromethyl)- phenothiazine and 6 grams ofN-methylmorpholine in anhydrous benzene, there is added dropwise asolution of l-adamantylacetyl chloride (prepared by treatment of 9.7grams of l-adamantylacetic acid with thionyl chloride) in anhydrousbenzene. The reaction mixture is then refluxed for 1 hour and cooled.The precipitated N-methyl morpholine hydrochloride is removed by filtration and the benzene solution extracted several times with dilutehydrochloric acid. The benzene solution is then dried over anhydrousmagnesium sulfate, filtered and concentrated under reduced pressure toyield the desired 10 [3-'( l-adamantylacetarnide -propyl] -2-(trifluoromethyl) phenothiazine.

b) Preparation of 10 {3-[2-(1-adamantyl)ethylamino] propyl}2-(trifluoromethyl)phenothiazine hydrochloride-To 3.8 grams of lithiumaluminum hydride in 200 ml. of anhydrous ether is added dropwise asolution of 10 [3-( l-adamantylacetamido propyl] -2-(trifluoromethyl)phenothiazine in anhydrous ether. The mixture isrefluxed for 1 hour after the addition is completed and is then cooledin ice water and treated cautiously with 2.5 ml. of water, followed by2.5 ml. of 20% aqueous sodium hydroxide. The mixture is filtered, driedover anhydrous potassium carbonate, treated With decolorizing charcoaland filtered. The filtrate is treated with an etheral solution ofhydrogen chloride until the pH of the solution is below 3 and theprecipitated solid is filtered. The hydrochloride of10-{3-[2-(1-adamantyl)ethylamino]propyl} 2(trifluoromethyl)phenothiazine thus obtained may be recrystallized froma mixture of absolute alcohol and anhydrous ether.

What is claimed is:

1. A compound selected from the group consisting of a base of theformula H F-OH: CH2

\ 0 I I 2) in t linver alkylene 7 8 lower alkyl and lower alkoxy; Z is amember of the 5. A compound of the formula group consisting of -N -N N-in and N-lower alkyl (R4) lower alkylene R is a member of the groupconsisting of hydrogen and OF3 lower alkyl, m is an integer from 0 to 7,and n is an integer from 1 to 2, a pharmaceutically acceptableacid-addition salt thereof, A compound of tha formula and apharmaceutically acceptable quaternary ammonium salt thereof.

2. A compound of the formula liawer alkylene N -lower alkyl loweralkylene N-lower alkyl CFB V liawer alkylene s 1; 7. A compound of theformula @513 I N-l 1k 1 3. A compound of the formula owera y loweralkylene halo 8. A compound of the formula I lower alkylene III-loweralkyl 1 |1wer alkylene N 1(:)W6! alkylene l |I-lower alkyl \s lrlnveralkylene halo 4. A compound of the formula \s/ 9. A pharmaceuticallyacceptable acid-addition salt of 30 a compound of claim 5.

10. A pharmaceutically acceptable acid-addition salt of a compound ofclaim 7.

11. 10 [3 (N-methyl-l-adamantylamino)propyl1-2- (trifluoromethyl)phenothiazine. 5 12. 10 [2 (N-methyl-1-adamantylamino)ethyl]-2- 2alkylene chlorophenothiazine. NH 13. 10 [2 (N ethyl 3methyl-l-adamantylamino)- I ethyl] -2-chlorophenothiazine. loweralkyleue 14. 10 {3 [4 (1 adamantylmethyl)-1-piperazinyl]- /1lI\propyl}-2-(trifluoromethyl)phenothiazine. G [D No references cited.

\S/ WALTER A. MODANCE, Primary Examiner.

HARRY I. MOATZ, Assistant Examiner.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF A BASE OF THE FORMULA 